Protein design with hierarchical treatment of solvation and electrostatics

A detailed treatment of the electrostatic energy of biomolecules in solution is used for two applications that require consideration of large numbers of states: multiple-site titration and protein design. The continuum electrostatic model is combined with covalent, van der Waals, and non-polar energy terms, and the statistical mechanical basis for this model is reviewed. Multiple-site titration is modeled with four titratable residues of the protein barstar. A full enumeration of the titration states is used to predict pH-dependent properties of the system, and the effects of several simplifying assumptions are evaluated. The analytical continuum electrostatics (ACE) method, a computationally inexpensive approximation of the electrostatic free energy, is evaluated in the context of predicting group terms of the binding free energy. A primary source of error in the ACE prediction of atomic solvation energies is identified and ameliorated. A procedure is developed which optimizes the parameters of the ACE method in order to minimize its errors as compared to finite-difference solution of the linearized Poisson-Boltzmann equation. Parameter sets optimized on a "testing" biomolecular binding system yield reduced average errors for related biomolecular systems. Finally, a protein design method is developed which uses the dead-end elimination and A* discrete search algorithms to systematically search large numbers (10²⁴) of structures, varying the proteinsequence and the side chain conformation at all selected residues.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Physics.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2002

Author dc:creator

• Hanf, Karl J. M. (Karl John Mortley), 1969-

Advisor dc:contributor.advisor

• Brice Tidor and Alexander van Oudenaarden.

• Physics.

Statement dc:rights

• M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/29223

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/29223